Epigenome-wide change and variation in DNA methylation in childhood: trajectories from birth to late adolescence.
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ABSTRACT:
SUBMITTER: Mulder RH
PROVIDER: S-EPMC8033147 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Asthma heritability has only been partially explained by genetic variants and is known to be sensitive to environmental factors, implicating epigenetic modifications such as DNA methylation in its pathogenesis.Using data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC), we assessed associations of asthma and wheeze with DNA methylation at 7.5 and 16.5 years, at over 450,000 CpG sites in DNA from the peripheral blood of approx. 1000 participants. We used Mendelian randomization (MR), a method of causal inference that uses genetic variants as instrumental variables, to infer the direction of association between DNA methylation and asthma.We identified 302 CpGs associated with current asthma status (FDR-adjusted P value <?0.05) and 445 with current wheeze status at 7.5 years, with substantial overlap between the two. Genes annotated to the 302 associated CpGs were enriched for pathways related to movement of cellular/subcellular components, locomotion, interleukin-4 production and eosinophil migration. All associations attenuated when adjusted for eosinophil and neutrophil cell count estimates. At 16.5 years, two sites were associated with current asthma after adjustment for cell counts. The CpGs mapped to the AP2A2 and IL5RA genes, with a -?2.32 [95% CI -?1.47, -?3.18] and -?2.49 [95% CI -?1.56, -?3.43] difference in percentage methylation in asthma cases respectively. Two-sample bi-directional MR indicated a causal effect of asthma on DNA methylation at several CpG sites at 7.5 years. However, associations did not persist after adjustment for multiple testing. There was no evidence of a causal effect of asthma on DNA methylation at either of the two CpG sites at 16.5 years.The majority of observed associations are driven by higher eosinophil cell counts in asthma cases, acting as an intermediate phenotype, with important implications for future studies of DNA methylation in atopic diseases.
| S-EPMC5640901 | biostudies-other
Project description:The occurrence of seizures in childhood is often associated with neurodevelopmental impairments and school underachievement. Common genetic variants associated with epilepsy have been identified and epigenetic mechanisms have also been suggested to play a role. In this study, we analyzed the association of genome-wide blood DNA methylation with the occurrence of seizures in ~ 800 children from the Avon Longitudinal Study of Parents and Children, UK, at birth (cord blood), during childhood, and adolescence (peripheral blood). We also analyzed the association between the lifetime occurrence of any seizures before age 13 with blood DNA methylation levels. We sought replication of the findings in the Generation R Study and explored causality using Mendelian randomization, i.e., using genetic variants as proxies. The results showed five CpG sites which were associated cross-sectionally with seizures either in childhood or adolescence (1-5% absolute methylation difference at pFDR < 0.05), although the evidence of replication in an independent study was weak. One of these sites was located in the BDNF gene, which is highly expressed in the brain, and showed high correspondence with brain methylation levels. The Mendelian randomization analyses suggested that seizures might be causal for changes in methylation rather than vice-versa. In conclusion, we show a suggestive link between seizures and blood DNA methylation while at the same time exploring the limitations of conducting such study.
| S-EPMC6950851 | biostudies-literature
Project description:Background:DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.Methods:We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18?years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.Results:DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P?<?1.06?×?10-7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment?=?1; childhood Penrichment?=?2.00?×?10-4; adolescence Penrichment?=?2.10?×?10-7).Conclusions:There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.
| S-EPMC7687793 | biostudies-literature
Project description:ImportanceThe understanding of the development of psychopathology has been hampered by a reliance on cross-sectional data and symptom- or disorder-centered methods. Person-centered methods can accommodate both the problems of comorbidity and the movement between different psychopathological states at different phases of development.ObjectiveTo examine the profiles and map the trajectories of psychopathology from early childhood to late adolescence.Design, setting, and participantsThis cohort study used 2 longitudinal nationally representative community-based cohorts from the Growing Up in Ireland study covering developmental periods from early childhood to late adolescence. Data in this investigation came from children and their families who participated in all waves of cohorts recruited in 2008 (children ages 3, 5, and 9 years) and 1998 (adolescents ages 9, 13, and 17 or 18 years). Both samples were weighted to account for representation and attrition. Latent transition analyses were used to map the trajectories of psychopathology. Data were analyzed between October 2020 and September 2021.Main outcomes and measuresPsychopathology was measured using the Strengths and Difficulties Questionnaire at all ages in both samples.ResultsA total of 13 546 individuals were included in the analyses. In the child cohort, mean (SD) age was 3.0 [0.01] years; 3852 (51.3%) were male participants. In the adolescent cohort, mean age was 9.0 (0.1) years; 3082 (51.0%) were male participants. Four profiles were identified in both cohorts that could be broadly labeled as no psychopathology (incidence range, 60%-70%), high psychopathology (incidence range, 3%-5%), externalizing problems (incidence range, 15%-25%), and internalizing problems (incidence range, 7%-12%). Transition between the profiles was common in both cohorts, with 3649 of 7507 participants (48.6%) in the child cohort and 2661 of 6039 participants (44.1%) in the adolescent cohort moving into 1 of the 3 psychopathology profiles at some point in development. Transition to the high psychopathology profile was most often preceded by externalizing problems. Approximately 3% to 4% of the sample had persistent psychopathology (child cohort, 203 participants [2.7%]; adolescent cohort, 216 participants [3.6%]). All psychopathology profiles were more common in boys in early life but, by late adolescence, girls were more likely to have internalizing problems. In a cross-cohort comparison at age 9, there were differences in the sex distributions of the profiles between the samples.Conclusions and relevanceUsing person-centered methods, this study demonstrated that from early life young peoples' experience of psychopathology is dynamic-they can move between different mental health problems; for most children, these problems are transient, but a small proportion (fewer than 5%) have persistent difficulties. In the context of finite resources, optimizing care requires the early identification of those with persistent phenomena.
| S-EPMC9092205 | biostudies-literature
Project description:BackgroundReports on body mass index (BMI) trajectories from childhood into late adolescence, their determinants, and subsequent cardiometabolic risk markers, particularly among European populations have been few. Moreover, sex-specific investigation is necessary considering the sex difference in BMI, and the sex-specific association between BMI and some cardiometabolic risk markers.MethodsUsing a sample from the DOrtmund Nutritional and Anthropometric Longitudinally Designed study, we explored sex-specific trajectories of the BMI standard deviation score (SDS) from 4 to 18 years of age in 354 males and 335 females by latent (class) growth models. The determinants of trajectory were assessed by logistic regression. We identified cardiometabolic risk markers that were highly associated with BMI SDS trajectory by random forest regression, and finally we used generalized linear models to investigate differences in the identified cardiometabolic risk markers between pairs of trajectories.ResultsWe observed four: 'low-normal weight', 'mid-normal weight', 'high-normal weight', and 'overweight', and three: ''low-normal weight', 'mid-normal weight', and 'high-normal weight' trajectories in males and females, respectively. Higher maternal prepregnancy BMI was associated with the 'overweight' trajectory, and with 'high-normal weight' trajectory in both sexes. In addition, employed mothers and first-born status were associated with 'high-normal weight' trajectory in females. BMI SDS trajectory was associated with high-density lipoprotein-cholesterol and interleukin-18 (IL-18) in males, and diastolic blood pressure and interleukin-6 (IL-6) in females. However, only males following the 'overweight' trajectory had significantly higher IL-18 when compared to their 'low-normal weight' counterpart.ConclusionsWe identified sex-specific distinct trajectories of BMI SDS from childhood into late adolescence, higher maternal prepregnancy BMI as a common determinant of the 'high-normal weight' and 'overweight' trajectories, and 'overweight' trajectory being associated with elevated IL-18 in late adolescence-young adulthood. This study emphasizes the role of maternal prepregnancy BMI in overweight, and highlights IL-18 as a cardiometabolic signature of overweight across life.
| S-EPMC6339359 | biostudies-literature
Project description:BackgroundEpigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis.ObjectiveWe sought to identify differential DNA methylation in newborns and children related to childhood asthma.MethodsWithin the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions.ResultsIn newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.ConclusionNovel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.
| S-EPMC6556405 | biostudies-literature
Project description:ObjectiveA mother-child dyad trajectory model of weight and body composition spanning from conception to adolescence was developed to understand how early life exposures shape childhood body composition.MethodsAfrican American (49.3%) and Dominican (50.7%) pregnant mothers (n = 337) were enrolled during pregnancy, and their children (47.5% female) were followed from ages 5 to 14. Gestational weight gain (GWG) was abstracted from medical records. Child weight, height, percentage body fat, and waist circumference were measured. GWG and child body composition trajectories were jointly modeled with a flexible latent class model with a class membership component that included prepregnancy BMI.ResultsFour prenatal and child body composition trajectory patterns were identified, and sex-specific patterns were observed for the joint GWG-postnatal body composition trajectories with more distinct patterns among girls but not boys. Girls of mothers with high GWG across gestation had the highest BMI z score, waist circumference, and percentage body fat trajectories from ages 5 to 14; however, boys in this high GWG group did not show similar growth patterns.ConclusionsJointly modeled prenatal weight and child body composition trajectories showed sex-specific patterns. Growth patterns from childhood though early adolescence appeared to be more profoundly affected by higher GWG patterns in females, suggesting sex differences in developmental programming.
| S-EPMC8957403 | biostudies-literature
Project description:While DNA methylation plays a role in T-helper (Th) cell maturation, its potential dysregulation in the non-atopic Th1-polarized systemic inflammation observed in obesity-associated asthma is unknown. We studied DNA methylation epigenome-wide in peripheral blood mononuclear cells (PBMCs) from 8 obese asthmatic pre-adolescent children and compared it to methylation in PBMCs from 8 children with asthma alone, obesity alone and healthy controls. Differentially methylated loci implicated certain biologically relevant molecules and pathways. PBMCs from obese asthmatic children had distinctive DNA methylation patterns, with decreased promoter methylation of CCL5, IL2RA and TBX21, genes encoding proteins linked with Th1 polarization, and increased promoter methylation of FCER2, a low-affinity receptor for IgE, and of TGFB1, inhibitor of Th cell activation. T-cell signaling and macrophage activation were the two primary pathways that were selectively hypomethylated in obese asthmatics. These findings suggest that dysregulated DNA methylation is associated with non-atopic inflammation observed in pediatric obesity-associated asthma.
| S-EPMC3712321 | biostudies-literature
Project description:Vitamin D deficiency is associated with hypertension in adults. It is unknown to what degree vitamin D status in early life can affect blood pressure (BP) a decade later. This study investigated the effect of vitamin D trajectory through early life on systolic BP (SBP) in childhood. This is a prospective birth cohort study of 775 children enrolled from 2005 to 2012 and followed prospectively up to age 18 years at the Boston Medical Center, Boston, MA. Persistent low vitamin D status is defined as plasma 25(OH)D <11 ng/mL at birth and <25 ng/mL in early childhood. Elevated SBP is defined as SBP ≥75th percentile. Low vitamin D status at birth was associated with higher risk of elevated SBP at ages 3 to 18 years: odds ratio, 1.38; (95% CI, 1.01-1.87) compared to those with sufficient vitamin D. Low vitamin D status in early childhood was associated with a 1.59-fold (95% CI, 1.02-2.46) higher risk of elevated SBP at age 6 to 18 years. Persistent low vitamin D status from birth to early childhood was associated with higher risk of elevated SBP (odds ratio, 2.04; [95% CI, 1.13-3.67]) at ages 3 to 18 years. These results suggest that low vitamin D status and trajectory in early life were associated with increased risk of elevated SBP during childhood and adolescence. Our findings will help inform future clinical and public health strategies for vitamin D screening and supplementation in pregnancy and childhood to prevent or reduce risk of elevated BP across the lifespan and generations.
| S-EPMC6938578 | biostudies-literature
Project description:OBJECTIVES:Leptin is a hormone produced by adipose tissue that promotes satiety, and some evidence suggests that greater early life leptin exposure prevents excessive adiposity gain in later life. However, few studies have analyzed dynamic changes in leptin throughout childhood in relation to later cardio-metabolic health. Our study aims to identify distinct leptin trajectories in childhood, and to examine their associations with cardio-metabolic outcomes in adolescence. METHODS:Among children in the Project Viva cohort born 1999-2002 in Massachusetts, we used latent class growth models to identify leptin trajectories independent of maternal BMI, child sex, race/ethnicity, size at birth and current age and size among 1360 children with leptin measured at least once at birth, early childhood (mean 3.3?±?SD 0.3?years), or mid-childhood (7.9?±?0.8?years). At research visits in early adolescence (13.2?±?0.9?years), we assessed cardio-metabolic outcomes including adiposity measures, fasting biomarkers, and blood pressure among 855 children. We then applied multiple regression models to examine associations of the leptin trajectories with these cardio-metabolic outcomes in early adolescence, adjusting for child age at outcome, maternal age, education, prenatal smoking and glucose, total gestational weight gain and paternal BMI. RESULTS:The latent class growth model identified 3 distinct leptin trajectories: "low stable" (n?=?1031, 75.8%), "high-decreasing" (n?=?219, 16.1%) and "intermediate-increasing" (n?=?110, 8.1%). In adjusted models, the intermediate-increasing leptin trajectory was associated with higher early adolescence adiposity measures (e.g. BMI z-score: 0.62?units; 95% confidence interval: 0.28, 0.96 and odds of obesity: 2.84: 1.17, 6.94), but lower systolic blood pressure (-0.46 z-score units; -0.74, -0.18), compared to the low-stable group. CONCLUSIONS:Our findings on leptin trajectories in childhood suggest important differences and associations with later metabolic outcomes.
| S-EPMC6366620 | biostudies-literature